Many organs and glands in the body contain smooth muscles that differ from skeletal muscle in smooth muscles are not under voluntary control and do not have a striated or banded appearance under the light microscope. These smooth muscles lack striations because their contractile filaments are not organized in regular arrays of aligned sarcomeres. Smooth muscles are specialized for long, slow contractions. Rather than taking instructions from motor neurons with cell bodies in the central nervous system, they are controlled by nerve fibers of the autonomic nervous system and by circulating hormones.
Smooth muscles perform a wide variety of functions. They control the diameter of arterioles and thus help regulate pressure. They form muscular sphincters at branches of the vascular tree and thus determine the distribution of blood to different capillary beds. Gastrointestinal sphincters control passage of intestinal contents from one section of the gut to the next. Smooth muscles regulate the size and internal pressure in hollow organs such as the urinary bladder and the uterus. Smooth muscles vary greatly in electrical activity, degree of automaticity, innervation, response to the circulating hormones and drugs, and extent of cell-to-cell coupling. (For a review of smooth muscles, see Stephens, N. L., Smooth Muscle Contraction, New York, M. Dekker, (1984)).
In unitary smooth muscle, contraction is synchronized so that the muscle acts as a unit, all fibers either contracting or resting. Unitary muscles are spontaneously active, display electrical pacemaker activity, and respond to stretch with increased activity. The innervation density is low, and the cells are tightly coupled electrically through gap junctions so that activity, once initiated, spreads promptly from cell to cell. The multicellular muscle acts as a single unit. Unitary smooth muscle thus resembles cardiac muscle more closely than striated muscle. Examples are the gut and uterus, organs that generate and propagate their own slow, rhythmic movements.
Time release delivery of drugs to a smooth muscle tissue or an organ is desired where there is a requirement for long-term administration of the drug to the tissue or organ. In addition, it is often advantageous to be able to deliver a drug directly to the site which needs to be treated and thereby avoid systemic administration of the drug. This is especially true where the drug may be harmful to certain other tissues or organs if administered systemically. Localized delivery would allow one to deliver high concentrations of the desired drug to a specific region of the body and yet not harm other tissues and organs.
Currently available therapies designed to externally regulate the contraction of internal organs are limited to electro-stimulation of specific diseased organ and/or systemic administration of musculotropic agents and/or neurochemicals. The implantation of a permanent electro-stimulator exposes patients to potential risks associated with major surgery and general anesthesia. The malfunctioning or infection of the electro-stimulation implant can further complicate or reverse the prognosis of these patients.
It is well-known that systemic administration of neurochemicals and/or musculotropic agents often adversely affects other non-diseased organs and tissues. The possible side effects can include dry mouth, blurred vision, mydriasis, tachycardia, drowsiness and constipation. In general, patients with glaucoma or a heart condition are excluded from systemic administration of these types of agents. Thus, the localized controlled administration of neurochemicals and/or musculotropic agents would optimize their effects on the targeted organs without significantly affecting other organs or nerve systems.
Several patents describe short-term delivery compositions and devices. U.S. Pat. No. 4,913,903 discloses a biodegradable polymer which can be admixed with a therapeutic agent and implanted into the body allowing short-term release of a therapeutic agent. The polymer is based upon two polyorthoesters and forms a solid polymer. The polymer disclosed in the '903 patent is designed to release chemotherapeutic agents over a relatively short period of time such as the convalescent period after surgery. The biodegradable polymer disclosed in the '903 patent would not be useful in the situation where long-term administration, i.e., one to two years, is necessary.
U.S. Pat. No. 4,871,542 discloses a method and apparatus for delivering therapeutic agents to the interior of the bladder and the urinary tract. The device disclosed in the '542 patent is a porous, minicellular polymeric container which acts as a reservoir for a therapeutic agent. The size of the minicellular pores regulates the rate of diffusion of the therapeutic agent. The device described in the '542 patent would not be suitable for implantation into a tissue for the long-term administration of a therapeutic agent.
U.S. Pat. No. 4,775,659 discloses an injectable, time-release formulation comprising a therapeutic agent, an oil and a suitable glyceride release modifying agent. The composition is injected intramuscularly, and the therapeutic agent is released over a period of days. The formulation described in the '659 patent would not be appropriate for the long-term delivery of a therapeutic agent to a tissue or organ.
U.S. Pat. No. 4,792,448 discloses a device wherein the matrix material is made of an inert material which either dissolves into the surrounding fluid or is insoluble and retains its original shape. To achieve long-term delivery of a therapeutic agent, the device disclosed in the '448 patent would be too large to be used as an injectable implant.
Finally, U.S. Pat. No. 4,725,442 discloses injectable microdroplets containing water-insoluble drugs. The preferred use of the microdroplets is the localized, time-release delivery of anesthetics. Again, the release of the water-insoluble drug from the microdroplets is disclosed as being useful only for a period of days. The microdroplets disclosed in the '442 patent would not be suitable for release of a biologically active agent over a period of months to years.
What is needed is an injectable device which can be implanted directly into the target tissue and which is capable of releasing a biologically active agent over a period of time. Such an injectable device would be particularly effective in treating patients with bladder instability etiology.